MDMA and Ecstasy

by Gerald Valentine, M.D.

The use of the illicit drug Ecstasy is a global phenomenon.
Despite harsher legal sentencing and widely publicized reports
of neurotoxicity and fatalities associated with Ecstasy
exposure, the prevalence of its use in the United States is
increasing among young adults (Johnston et al., 2000.
The U.S. Drug Enforcement Agency (DEA) has estimated that
750,000 tablets of Ecstasy are used every weekend in New York
and New Jersey alone. Ecstasy culture has surpassed the
LSD-centered psychedelic movement of the 1960s, in both its
longevity and number of users. As was the case for LSD, media
distortions and sensationalistic accounts of catastrophic
reactions have contributed to misunderstandings about Ecstasy.

The principle constituent of Ecstasy --
3,4-methylenedioxymethamphetamine (MDMA) -- can produce robust
deleterious effects on serotonergic functioning in animals,
including serotonin depletion and the degeneration of
serotonergic nerve terminals (Ricaurte et al., 2000). Whether
neurotoxicity also occurs in humans is unknown, but emerging
evidence indicates that repeated Ecstasy exposure results in
performance decrements in measures of neurocognitive function,
which may be a manifestation of neurotoxicity (Morgan, 1999;
Rodgers, 2000).

The specter of millions of Ecstasy users with severely
disrupted serotonergic systems raises complicated public
health issues with direct relevance to psychiatry. Given the
neurotoxic potential and unknown long-term consequences of
MDMA exposure, the recent approval by the U.S. Food and Drug
Administration for a clinical trial of MDMA-assisted
psychotherapy may be perplexing to those unfamiliar with its
unique psychoactivity and history of therapeutic use. The
purpose of this article is to provide psychiatrists with basic
information about MDMA's pharmacology and addictive potential
and to summarize data gathered from the clinical and
recreational contexts of MDMA use that have particular
relevance to clinical practice. In addition, a brief
historical account of MDMA is presented to provide a context
for understanding the complicated medical and social issues
centered around MDMA.

History of MDMA

The first report of MDMA's pharmacological effects in
humans appeared in 1978, which described an "easily controlled
altered state of consciousness with emotional and sensual
overtones" that was devoid of a hallucinatory component or
psychological sequelae. The intoxication lasted several hours
and was accompanied by sympathomimetic effects (Shulgin and
Nichols, 1978). The drug's ability to reduce defensiveness and
anxiety was recognized as potentially useful in therapy.

From the 1970s to the mid-1980s, MDMA was used legally as
an adjunct to psychotherapy by a slowly expanding group of
therapists. This therapeutic community was aware of the
governmental restrictions imposed on research with LSD and
other psychedelics once their use spread to a recreational
context. Consequently, most therapists agreed to continue
quietly using MDMA and only informal studies were performed.

However, by the early 1980s, MDMA was transformed into a
commercial product marketed as "Ecstasy" that could be
purchased by phone or at night clubs. Both the therapeutic
community and politicians were alarmed by this uncontrolled,
conspicuous consumption. In 1984, Sen. Lloyd Bentsen (D-Texas)
formally requested that the DEA make MDMA illegal, and two
years of public debate ensued during formal administrative law
hearings. Advocates of MDMA testified to its relative safety
and unique therapeutic utility, while witnesses for the DEA
expressed concern over the abuse and neurotoxic potential of
3,4-methylenedioxyamphetamine (MDA), an analogue and
metabolite of MDMA.

In July 1985, the DEA placed MDMA into Schedule I (the most
restrictive category) of the Controlled Substances Act for one
year on an emergency basis. On May 22, 1986, the DEA's
administrative law judge recommended that MDMA be placed into
Schedule III, concluding that there was sufficient evidence
for an acceptable medical use and safe utilization under
medical supervision. However, the DEA administrator overruled
this advisement. In 1988, MDMA was placed permanently into
Schedule I. This effectively ended its therapeutic use and
severely curtailed controlled clinical studies. However, it
had no effect on recreational use.

Chemistry and Pharmacology

MDMA is a phenethylamine, a chemical class based on a core
molecular configuration of a benzene ring and an ethylamine
side chain. The varied biological effects of phenethylamines
are dependent on the specific chemical groups attached to this
core structure. Examples of psychoactive phenethylamines are
the monoamine neurotransmitters; the pharmaceuticals
fenfluramine (Pondimin [voluntarily withdrawn from the U.S.
market in 1997]), dextroamphetamine (Dexedrine) and
venlafaxine (Effexor); and the hallucinogen mescaline.

The pharmacological effects of MDMA are complex, involving
serotonergic, dopaminergic and noradrenergic systems. The
primary effect is to acutely increase synaptic serotonin
levels, followed by a prolonged course of serotonin depletion
(White et al., 1996). It appears to simultaneously promote the
release and block the reuptake of serotonin through serotonin
transporter dependent mechanisms (Berger et al., 1992; Nichols
et al., 1982; Rattray, 1991). It also promotes the release and
blocks the reuputake of dopamine, although to a lesser extent
(Nash and Brodkin, 1991; Pan and Wang, 1991). Amphetamine is
six times more potent a dopamine releaser than MDMA in an in
vitro assay of rat striatum (Kalix et al., 1988). MDMA has
relatively high affinity for the a2 adrenoceptor and the
noradrenergic transporter; this may account for
sympathomimetic effects (such as the acute increases in
systolic and diastolic blood pressure) seen after MDMA
administration (Lavelle et al., 1999; Lester et al., 2000;
Steele et al., 1987).

In addition, MDMA has weak affinity for 5-HT2A receptors and acutely inhibits
tryptophan hydroxylase (TPH), the rate-limiting enzyme in
serotonin synthesis (Battaglia et al., 1988; Stone et al.,
1986). The reversibility of TPH inhibition in reducing
conditions provided the first clue that MDMA can promote
oxidative changes in neuronal components (Stone et al., 1989).
Oxidative stress is a process during which the structure and
function of macromolecules are disrupted by highly energetic,
unstable chemical species with unpaired electrons (free
radicals). Free radicals are continuously made in vivo, and
the body has multiple protective antioxidant mechanisms. When
antioxidant capacity is overwhelmed, cell damage or death can
occur. Accumulating evidence indicates that under some
conditions, MDMA promotes oxidative stress, which may be an
important mechanism of serotonergic neurotoxicity (Aguirre et
al., 1999; Shankaran et al., 2001).

Although MDMA has been characterized as a hallucinogenic
amphetamine due to its structural similarity to mescaline and
amphetamine, it rarely induces hallucinatory experiences, nor
is it as potent a psychostimulant as amphetamine. In
controlled settings, 100 mg to 125 mg of oral MDMA induces a
subjective experience of heightened mood, increased
self-confidence, extroversion and emotional excitability. In
addition, moderate derealization, depersonalization and
intensified sensory perception commonly occur. Effects of MDMA
typically peak 15 minutes to 30 minutes after administration
and last between three hours to four hours.

Many of MDMA's psychological effects result from serotonin
release. Pretreatment with an intravenous infusion of the
selective serotonin reuptake inhibitor citalopram (Celexa)
blocks many of the characteristic psychological effects,
including heightened mood (Liechti et al., 2000a). Perceptual
changes are not affected by citalopram but are reduced by the
5-HT2A/C antagonist ketanserin, suggesting that the mild
hallucinogenic-like effects of MDMA are due to 5-HT2A agonist
activity (Liechti et al., 2000b). Dopamine also contributes to
MDMA's psychological effects, while the effects of
noradrenergic modulation are unknown.

Commonly reported acute side effects include anorexia,
sustained contraction of masticatory muscles (trismus),
impaired balance and difficulty concentrating. Although the
sample size in controlled experiments is small, the results
corroborate the reports of a low incidence of acute or
subacute psychiatric problems in patients treated during the
era of MDMA-assisted psychotherapy.

Psychiatric Complications

Many Ecstasy users may be exposing themselves to neurotoxic
regimens that result in long-lasting serotonergic degeneration
or, at the very least, acutely depleted serotonin levels. The
potential for increased serotonergically mediated
psychopathology is apparent.

The most commonly reported psychiatric problems in
individual case reports are psychosis, anxiety, panic disorder
and depression. Dysphoria and memory disturbances have been
reported at two and five days after binge Ecstasy use (Curran
and Travill, 1997). In a study of 150 Ecstasy users presenting
for substance-abuse treatment, 53% were diagnosed with a
neuropsychiatric problem (Schifano et al., 1998). A study
comparing heavy and light Ecstasy users to controls found
higher levels of paranoid ideation, psychoticism,
somatization, obsessionality, anxiety, hostility, phobic
anxiety, appetite disturbance, restless sleep and
impulsiveness in Ecstasy users (Parrott et al., 2000).

Although these studies are suggestive of increased
psychopathology secondary to Ecstasy use, establishing cause
and effect relationships is problematic due to significant
methodological limitations. Subjects are mainly polysubstance
users without established premorbid functioning. These studies
often have poorly matched or absent comparison groups and rely
on self-reported estimates of the amount of Ecstasy used.

Most studies lack toxicological or chemical analyses that
identify the actual drugs ingested, further complicating the
attribution of acute psychiatric problems to a specific drug.
In addition, the actual composition of the ingested drug may
be uncertain. Although most Ecstasy tablets contain MDMA,
other commonly identified ingredients include ketamine, MDA,
amphetamine, dextromethorphan or combinations of these drugs.
Some tablets contain inert ingredients, while others contain
phencyclidine (PCP).

These same limitations apply to most studies on cognitive
performance in Ecstasy users. To date, a clearly defined
psychiatric or neurological syndrome has not been attributed
to Ecstasy abuse. While it is a statistical certainty that
some Ecstasy users will present for psychiatric services, the
current available data shed little light on whether Ecstasy
use is a precipitant, modifier or consequence of psychiatric
illness.

Another clinical concern is the potential for diminished or
absent therapetic responses to psychotropic medications.
Several studies have demonstrated blunted serotonergic
neuroendocrine responses in Ecstasy users, suggesting that
central serotonergic dysfunction may also result in
subpopulations who are or will become treatment refractory
(Gerra et al., 2000; McCann et al., 1999). There have been no
studies examining treatment responses in psychiatrically ill
Ecstasy users, and the risks of using psychiatric medications
in these patients are unknown. In cases of acute Ecstasy
intoxication with psychosis, neuroleptics should be avoided,
as they could accentuate hyperthermic reactions or promote
conditions favorable to the formation of neuroleptic malignant
syndrome (Green et al., 1995).

Extrapolation to humans suggests that MDMA has less
addictive potential than psychostimulants but may sensitize
Ecstasy users to the reinforcing effects of stimulants. A
small subset of compulsive Ecstasy users is likely to meet
criteria for dependence (Jansen, 1999). However, Ecstasy use
does not appear to result in a clearly defined dependence or
withdrawal syndrome for most users. Tolerance to the euphoric
effects quickly develops, with repeated use leaving unpleasant
sympathomimetic side effects from escalating doses. This
generally limits frequent dosing. Chronic, high-dose Ecstasy
use is likely to have a withdrawal syndrome similar to that
observed in cocaine and amphetamine abusers.

Treatment Model

Last November, the FDA approved a Phase II clinical trial
designed to study the safety and efficacy of MDMA-assisted
psychotherapy in the treatment of chronic posttraumatic stress
disorder (PTSD). This is the first approved protocol designed
to explore the therapeutic use of MDMA. Researchers at the
Medical University of South Carolina intend to employ a
treatment model that evolved during the hundreds of
MDMA-assisted therapeutic sessions performed prior to MDMA's
criminalization. Unlike earlier psychedelic treatment models,
which used potent hallucinogenic drugs that radically changed
the patient's state of consciousness in unpredictable ways,
the subjective state associated with MDMA is fairly
predictable and easily controlled.

Commonly reported psychological effects of MDMA include
feeling states of empathy, compassion, acceptance,
forgiveness, openness and caring (Adamson, 1985). MDMA appears
to mitigate conditioned fear responses to perceived emotional
threats, allowing patients to examine their own lives and
interpersonal relationships from a position of security and
love. Patients experience a state of reduced defensiveness
that promotes self-disclosure and trust for several hours
after ingestion, thereby strengthening the therapeutic
alliance (Greer and Tolbert, 1990).

MDMA may be the prototype for a novel category of
psychoactive drugs characterized as "enactogens," based on
their unique psychological and pharmacological profile
(Nichols and Oberlender, 1990). The descriptor enactogen,
derived from the Latin root tactus (touch) and the Greek roots
gen (to produce) and en (within), attempts to capture the
apparent ability of these drugs to facilitate a patient's
access to painful emotional states that are ordinarily heavily
defended.

In addition to PTSD, a variety of other psychiatric
difficulties including depression, anxiety, addiction, eating
disorders and chronic interpersonal problems were reported to
be safely and effectively treated with MDMA (Downing, 1986;
Greer and Tolbert, 1990). These claims await corroboration
from controlled, clinical studies.

Conclusion

The widespread use of Ecstasy has direct and profound
implications for psychiatry. The millions of youths ingesting
unknown combinations of powerful drugs in conditions that are
likely to accentuate adverse reactions and neurotoxicity is a
daunting public health problem. The true extent of psychiatric
morbidity associated with Ecstasy use remains to be
determined. Presently, an empirically based foundation for
guiding treatment decisions in Ecstasy-using patients does not
exist and should be a focus of future investigation.

Likewise, MDMA's treatment efficacy and tolerability has
not been empirically established. It is critical for
psychiatrists to keep contexts of use in mind when evaluating
both patients and the scientific literature. In some
situations, MDMA appears to be a human neurotoxin while in
others, a unique and useful medicine. Carefully designed
prospective clinical experiments are needed for a truly
objective evaluation of MDMA's risks and therapeutic
potential.

Dr. Valentine is a fourth-year psychiatry resident
in the Neuroscience Research Training Program at Yale
University.

References

Adamson S, ed. (1985), Through the Gateway of the Heart.
Accounts and Experiences With MDMA and Other Empathogenic
Substances. San Francisco: Four Trees Publications.

Kalix P, Yousif MY, Glennon RA (1988), Differential effects
of the enantiomers of methylenedioxymethamphetamine (MDMA) on
the release of radioactivity from (3H)dopamine-prelabeled rat
striatum. Research and Communications in Substance Abuse
9:45-52.